Aging-related morbidities have significantly increased due to the increase in human lifespan. The exponential surge in mortalities arising from cardiovascular disease (CVD) among the elder population strongly suggests that intrinsic cardiac aging itself is a risk factor. Endurance exercise has been shown to confer potent cardioprotection against CVD in the elderly. Recently, five months of endurance exercise was found to strongly attenuate the accelerated cardiac aging phenotypes of a mitochondrial DNA mutator mouse (PolG), a model that exhibited grossly abnormal aging phenotypes, including cardiac hypertrophy, heart failure and fibrosis. Remarkably, by the end of the endurance training protocol, the severe cardiac hypertrophy associated with PolG mice was blunted and heart size was comparable to wild-type (WT) mice. However, the mechanism in which endurance exercise confers this cardioprotection is currently unknown. The transcriptional co-activator, PPAR gamma co-activator 1 (PGC-1), has emerged as a principal mediator of skeletal muscle adaptations in response to endurance exercise, including mitochondria biogenesis and angiogenesis. Furthermore, mouse models with PGC-1 overexpressed mitigate much of the systemic phenotypes of aging, even in the absence of exercise. Thus, this project will test the hypothesis that PGC-1 induction in skeletal muscles by endurance exercise mediates the secretion of certain factors, termed myokines, that act on the heart and confer cardioprotection against CVD. The first aim will assess if PGC-1 is necessary to prevent cardiac aging by crossing mouse models with PGC-1 deleted specifically in skeletal muscles to the PolG mutator mouse model. Cardiac morphology and function will be assessed after exercise to determine if PGC- 1 is required to observe the cardioprotection seen in endurance exercise. The second aim will determine if PGC-1 is sufficient to confer cardioprotection by crossing skeletal muscle-specific PGC-1 overexpressing mice to PolG mice. Cardiac morphology and function will be determined in the absence of exercise. Lastly, aim 3 will seek to characterize the effects of myokine secretion on the heart in response to exercise and PGC-1 induction. Conditioned media collected from PGC-1 overexpressing cells will be tested for induction of cardioprotective genes and improvement of contractility properties in adult rat cardiomyocytes in cell culture, along with protection against cardiac hypertrophy. These studies will provide considerable insight into the mechanism with which endurance exercise is able to confer potent cardioprotection against cardiac aging. Such insights will provide novel avenues of therapeutic intervention against CVD. PUBLIC HEALTH RELEVANCE: Intrinsic cardiac aging itself has been found to be a risk factor for cardiovascular mortality. Endurance exercise confers potent cardioprotection against cardiovascular disease (CVD) in the elderly. How exercise, which largely involves contraction of the skeletal musculature, can have such a profound effect on the heart, remains unclear. These studies will offer insight into the mechanisms responsible for the strong cardioprotection offered by exercise, and may present new therapeutic avenues with which to counter CVD.